Concurrent administration of donezepil HCl and risperidone in patients with schizophrenia: Assessment of pharmacokinetic changes and safety following multiple oral doses

Abstract

Aim: This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs. Methods: Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1-4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (Cmax, t max and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7). Results: The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC0-24 h = 329.0 ± 17.2 ng·h ml-1) and controls taking donepezil HCl alone (AUC0-24 h = 354.7 ± 28.2 ng·h ml-1). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC0-12 h standardized by dose: risperidone = 59.6 ± 16.3 ng·h ml-1 at day 0, 56.0 ± 15.8 ng·h ml-1 at day 7; 9-OH risperidone = 162.1 ± 19.2 ng·h ml-1 at day 0, 163.3 ± 15.0 ng·h ml-1 at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration. Conclusions: These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.